Nuclear translocation of calcium/calmodulin-dependent protein kinase II{delta}3 promoted by protein phosphatase-1 enhances brain-derived neurotrophic factor expression in dopaminergic neurons. [Neurobiology]
July 10th, 2015 by Shioda, N., Sawai, M., Ishizuka, Y., Shirao, T., Fukunaga, K.
We previously reported that dopamine D2 receptor (D2R) stimulation activates calcium/calmodulin-dependent protein kinase II (CaMKII)δ3, a CaMKII nuclear isoform, increasing brain-derived neurotrophic factor (BDNF) gene expression. However, mechanisms underlying that activity remained unclear. Here, we report that CaMKIIδ3 is dephosphorylated at Ser332 by protein phosphatase-1 (PP1), promoting CaMKIIδ3 nuclear translocation. Neuro-2a cells transfected with CaMKIIδ3 showed cytoplasmic and nuclear staining, but staining was predominantly nuclear when CaMKIIδ3 was co-expressed with PP1. Indeed, PP1 and CaMKIIδ3 co-expression significantly increased nuclear CaMKII activity and enhanced BDNF expression. In support of this idea, chronic administration of the dopamine D2R partial agonist aripiprazole (APZ) increased PP1 activity and promoted nuclear CaMKIIδ3 translocation and BDNF expression in the rat brain substantia nigra. Moreover, APZ treatment enhanced neurite extension and inhibited cell death in cultured dopaminergic neurons, effects blocked by PP1γ knockdown. Taken together, nuclear translocation of CaMKIIδ3 following dephosphorylation at Ser332 by PP1 likely accounts for BDNF expression and subsequent neurite extension and survival of dopaminergic neurons.